Signal transducer and activator of transcription 3 (StatS) is a key signaling intermediate for cytokine receptors that regulate the survival, proliferation, and differentiation of myeloid progenitor cells. StatS is aberrantly active in many different types of cancer, including acute myeloid leukemia (AML), and is associated with poor outcome. Moreover, constitutively active StatS causes malignant transformation in vitro. Elucidating the precise functions of StatS is complicated by the existence of StatS in two isoforms: StatSa (full-length) and StatSp (truncated). Evidence from our lab and others suggests that StatSa inhibits apoptosis and promotes neutrophil development, while StatSp may modulate gene transcription by association with StatSa or other transcription factors. Our over-arching hypothesis is that StatSa and StatSp mediate distinct functions in normal and malignant myeloid cells. The specific aims of this Career Development Award are 1) to use StatS isoform-deficient hematopoietic stem cells to investigate the roles of the StatS isoforms in the development of normal myeloid cells, 2) to discover and study gene targets that are differentially regulated by the two isoforms, and 3) to examine the contribution of StatS to the malignant phenotype in transformed myeloid cells with gain-of-function c-kit mutations. Dr. Tweardy's lab is uniquely positioned to successfully carry out this important research. First, Dr. Tweardy has made significant contributions in StatS signal transduction and has ongoing research in this area. Second, the lab possesses two critical reagents: novel myeloid cell lines that conditionally overexpress either StatSa or StatSp, and transgenic mice that are deficient in StatSa or StatSp. Third, the expertise required to carry out this novel research is available within the lab and through extensive interactions with collaborators. Despite aggressive treatment, cure rates for AML remain low, and innovative approaches are needed. Understanding the functions of StatS isoforms in myelopoiesis and leukemogenesis will be crucial for directing future efforts at therapies targeted to signaling pathways, and for better assessing each patient's risk of treatment failure. Under the guidance of Dr. Tweardy, and with the superb resources available at Baylor College of Medicine, this award will lay the groundwork for a productive career as an independent physician-scientist in the area of myelopoiesis and myeloid leukemia.